Breast cancer causes the death of a quarter of a million women worldwide each year and is estimated to be the leading cause of death in women aged between 35 to 54, being second only to cardiovascular diseases in women aged over 55 (LOGAN W.P.D.: Cancer of the female breast. International mortality trends. W.H.O. Stat. Rep. 28:232, 1975).
Breast cancer accounts for 27% of all malignancies around the world. Historically, the first to discover the role played by endocrine treatment in breast cancer was BEATSON (1896) who observed that breast cancer in pre-menopausal women undergoes remission after oophorectomy.
This finding, subsequently confirmed by other scientists, supported the evidence that at least some breast tumors are directly dependent on hormones for their growth and created interest in the therapeutic approach of endocrine organ ablation for the purpose of removing the endogenous source of hormones.
As drugs specifically antagonizing the oestrogen action were discovered, they became an attractive alternative to surgical ablation.
Several antiestrogen compounds have been tested in pre- and post-menopausal women in phase I and II clinical trials. So far, Tamoxifen has proved to be the drug best approaching the effectiveness of surgical endocrine therapy and the one that is substantially free from serious side effects.
A comprehensive review of the therapeutic efficacy of antiestrogens in the treatment of breast cancer is LEGHA S. S. and CARTER S. K.: Anti-estrogens in the treatment of breast cancer. Cancer Treat. Rev. 3:205, 1976.
Another review more specifically related to clinical experience with Tamoxifen is that of PATTERSON J. S., et al: A review of the International clinical experience with Tamoxifen. Jpn. J. Cancer clin. 11 (Suppl.): 157, 1981.
Approximately one-third of women with breast cancer respond to antiestrogen-based hormonal therapy, while an increase up to 70% of response is expected in patients with receptor-rich tumors. In fact, estrogen receptor (ER) status has been demonstrated to be predictive of response in breast cancer patients--ALLEGRA J. C.: Reviews on Endocrine related cancer. (Paterson AHG, Lees A W eds) Suppl. 14:115, 1984.
Interferons are a well-known family of proteins which have been shown to possess both antiviral and cell growth inhibitory effects.
Human interferons are grouped into three classes based upon differences in biological and immunological properties as well as molecular structures.
Interferons are also classified, in accordance with their chemical sensitivity to acid pH, into two types:
TYPE I: Acid-stable (alpha from leukocytes, alpha from lymphoblasts, beta from fibroblasts); PA1 TYPE II: Acid-labile (gamma from lymphocytes).
Interferons have a wide range of cellular effects on cancer, as well as on normal cells, including such effects on cell phenotype as antigen expression, cell receptors and so on.
The mechanism by which interferons regulate human cell growth has not been completely elucidated.
In particular, very few data are available concerning the antiproliferative activity of interferons on human mammary neoplastic cells and little is known about the factors determining sensitivity of these cells to the interferon action--BORDEN E. C., et al: Comparative antiproliferative activity in vitro of natural interferons for diploid and transformed human cells. Cancer Res. 42:4948-4953, 1982. --STRAYDER D. R., et al: Antiproliferative effect of natural beta interferon on fresh tumor cells analyzed in a clonogenic assay. J. Interferon Res. 4:627-633, 1984.
Experimental evidence exists that type I IFN modifies the hormone receptor level in breast cancer tissue cells. POUILLART T., et al, in: "Administration of fibroblast interferon to patients with advanced breast cancer: possible effects on skin metastasis and on hormone receptors" (Eur. J. Cancer Clin. Oncol. 18:929-935, 1982) described the effect on human fibroblast interferon administered to patients with metastasised breast cancer and found an increase of the receptors for estrogens and progestogens.
DIMITROV N. V., et al, in: "Interferon as a modifier of estrogen receptor" (Ann. Clin. Lab. Sci. 14:32-39, 1984) demonstrated that human leukocyte interferon increases estrogen receptor activity in a cell homogenate of human breast cancer tissue.
Contradictory experimental evidence is that of MARTH Ch., et al, in: "Effects of human Interferon Alpha-2 and Gamma on proliferation, estrogen receptor content, and sensitivity to anti-estrogens of cultured breast cancer cells" (The Interferon System, Ed. F. Dianzani, G. B. Rossi, Serono Symposia Publs. from Raven Press, Vol. 24, 1985) who were unable to demonstrate any influence by interferon alpha on estrogen receptor content in cultured breast cancer cells. The conclusion thus reached by the authors is that estrogen action is independent of interferon since the growth inhibition by anti-estrogens is not affected by interferon treatment.